Chemokines are up-regulated in the brain of Alzheimer's disease patients and are produced after amyloid-beta[unreadable] stimulation of glial cells.Based on these initial findings, we propose the following hypothesis: 1) some (if[unreadable] not all) chemokines produced by the reactive glial cells protect neurons against the toxicity of amyloid-b[unreadable] peptide through activation of the cognate chemokine receptors. 2) Specific signaling pathways initiated by[unreadable] the chemokine receptors are involved in the chemokine receptor-mediated neuroprotection. 3) Chemokine[unreadable] receptors in the inflamed CNS become constitutively desensitized due to the over-stimulation of the[unreadable] receptors by the excessive chemokines and excitatory amino acids produced by the activated astrocytes and[unreadable] microglial cells, thus resulting in attenuation of the chemokine receptor-mediated neuroprotection in clinical[unreadable] settings, such as those occuring in Alzheimer's disease. I propose the following specific aims to test these[unreadable] hypotheses. Aim 1. To determine whether CXCR2 is involved in the protection against amyloid-b peptide-induced[unreadable] neuronal death using CXCR2 knock-out mice and a selective CXCR2 antagonist in transgenic mice[unreadable] overexpressing human mutant human amyloid precursor protein as experimental tools. Aim 2. To determine[unreadable] the signaling pathways of CXCR2 involved in the receptor-mediated neuroprotection against amyloid-b[unreadable] peptide -induced neuronal damage. . To examine the contribution of glutamate- and chemokine-induced[unreadable] receptor desensitization and impairment of receptor resensitization to the failure of CXCR2 overexpression in[unreadable] AD to protect against neurodegeneration: Several important fundamental understandings will result from our[unreadable] studies, all of which have signficance for the understanding of the pathogenesis of neurodegenerative[unreadable] disease and its therapeutic interruption or prevention. First, we will clarify the role of the CXCR2 receptor in[unreadable] neuroprotection from pathways activated by b-Amyloid protein, in vitro and in vivo, utilizing complementary[unreadable] morphological, functional and behavioral assessments. Second, we will test the hypothesis that chemokinemediated[unreadable] signaling relevant for neuroprotection is counteracted by NMDA via mechanisms related to[unreadable] interruption of CXCR2 recycling and regeneration of receptor sensitivity to endogenous chemokines[unreadable] produced in excess in pathological settings, providing evidence for useful strategies for therapeutic[unreadable] intervention in AD and other neurodegenerative diseases.[unreadable]